Poly(ADP-ribose)polymerase (PARP) which is enzyme in the cell's nucleus, is found in most of eukaryotic cells, and catalyzes the transfer of ADP-ribose unit to nuclear receptor protein using nicotinamide adenine dinucleotide (NAD+) as a substrate, and induces formation of homo-ADP-ribose polymer branched from protein-bound linear. PARP consists of 7 isozymes comprising PARP-1, PARP-2, PARP-3, PARP-4 (Vault-PARP), tankylase such as PARP-5 (TANK-I, TANK-2 and TANK-3), PARP-7, and PARP-10 [de la Lastra C A., et al., Curr Pharm Des., 13(9), 933˜962, 2007]. Among the above, nucleus enzyme Poly(ADP-ribose)polymerase-1 (PARP-1) is the main enzyme, and occupies 97% of the Poly(ADP-ribose)polymerase made in the brain [Strosznajder R. P., et al. Mol Neurobiol., 31, (1-3), 149˜167, 2005]. Among many functions of PARP, in particular PARP-1, the major function is to facilitate DNA repair by ADP-ribosylation and to regulate the number of DNA-repair proteins. The PARP activation in cells with huge scale of DNA damage results in significant decrease of NDA+ concentration and considerable deficiency. PARP-1 is 116 kDa nucleoprotein that includes three domains which comprise a N-terminal DNA binding domain containing two zinc fingers, an automatic modification domain, and a C-terminal catalytic domain. The Poly(ADP-ribose)polymerase enzyme synthesizes poly(ADP-ribose) which is a polymer with branched structure may be consisted of 200 of more units of ADP-ribose. The poly(ADP-ribose) protein receptor may be included directly or indirectly maintaining DNA integrity. These include histone, topoisomerase, DNA and RNA polymerase, DNA ligase, and Ca2+ and Mg2+-dependent endonuclease. PARP proteins are expressed in many tissues, in particularly high concentration in immune system, heart, brain and microorganism cell strains. Although the PARP proteins have minimum PARP activity does exist under general biological conditions, the PARP activity increases up to 500 times greater when DNA is damaged.
PARP activation and formation of poly(ADP-ribose) reaction products are caused by the DNA decay after exposure of chemotherapy, ionizing radiation, oxygen free radical, or nitric oxidant (NO). In DNA damage induced by radiotherapy or chemotherapy, the transmission process of ADP-ribose of the cells may contribute to resistance that can occur in various types during cancer treatment since it is related to the repair of the damaged DNA. Therefore, PARP inhibition can deter repair of DNA damage in the cells and can enhance the anti-cancer effect of the cancer therapy. Furthermore, recently it has been reported that the tankyrase, which binds to telomere protein TRF-1, the negative control factor of the telomere length, has the catalytic domain with a significant homogeny with the PARP, and has in vitro PARP activity. In addition, it has been suggested that function of the telomere in human cells is adjusted by the poly(ADP-ribosyl)ation. The PARP inhibitor is useful as a means of study of function to regulate the length of the telomere in the adjustment of telomere activity by tankyrase [B A., et al., Int J Biochem Cell Biol., 37, 1043˜1053, 2005]. For example, PARP inhibitor can be used for cancer treatment by shortening life cycle of immortalized cancer cells, or utilized as a cell life cycle regulator or an anti-aging medicine in view of the relationship between the length of the telomere and cell aging.
It has also been reported that the PARP inhibition can enhance the resistance in brain injury. Ischemic brain injury is generated by poly(ADP-ribose)polymerase activity-mediated exhaustion of NAD+ and resulting in energy deficiency [Endres M., et al., J. Cereb Blood Flow Metab., 17(11), 1143˜1151, 1997]. Regarding cerebral ischemia, activation of PARP according to DNA damage acts on apoptosis induced to seizure, brain damage and neurodegerative diseases. The apoptosis is considered to be generated as a result of energy decreases corresponding to NAD+ consumption due to PARP reaction catalyzed by enzymes, and DNA damage occurs due to an excessive amount of nitric oxidant generated as the nitric oxidant synthetase is activated by the products initiated by the glutamic acid released from the depolarized nerve endings. Lack of oxygen in neurons causes stroke or ischemic brain damage, and then the neuron releases a large amount of glutamate. The excessive amount of glutamate causes hyperstimulation (exitotoxicity) of N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainite, and metabotropic glutamate receptor (MGR), which opens ion channel and thus allows unregulated ion flow (e.g., permitting Ca2+ and Na+ into cells, causing K+ to release out of the cell), causing hyperstimulation of neurons. Hyperstimulated neurons causes more release of glutamate, generating feedback loop or domino effect and eventually causing cell damage or death through the generation of protease, lipase, and free radical. The over-activation of the glutamate receptors is related to a variety of neuropathic diseases including epilepsy, stroke, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, schizophrenia, chronic pain, ischemia, neuron damage after hypoxia, external injury, and neural damage.
The PARP inhibitor can be used for treatment of not only central nervous system disorders, but also disorders of peripheral nervous system such as neuropathic pain caused due to chronic constriction injury (CCI) of common sciatic nerve [Di Cesare Mannelli L., et al., Eur J Neurosci., 26(4), 820˜827, 2007]. The exact mechanism for the potential of the PARP inhibitor in treatment for the neuropathic pain has not been explained fully yet, but considered positively.
The PARP inhibitor also acts on the treatment of inflammatory symptoms such as arthritis [Szab C., et al., Proc. Natl. Acid. Sci. USA 95(7), 3867˜3872, 1998]. Poly(ADP-ribose) synthesis is included for induced expression of many genes which are essential for the inflammatory reactions. The PARP inhibitor inhibits formation of macrophagocyte, inducible nitric oxidant sythease (iNOS) from P-type selectin, and inter-cellular adhesion molecule-1 (ICAM-1) on endothelial cells. The above activity is a basis for the strong anti-inflammatory effect by the PARP inhibitor. Furthermore, the PARP inhibition can reduce necrosis by preventing translocation and infiltration of neutrophils into damaged tissues. Accordingly, the PARP inhibitor is useful for treatment of inflammatory symptoms.
The PARP inhibition is useful for protecting myocardinal ischemia [Szab C., Curr Vasc Pharmacol., 3(3), 301˜303, 2005] and reperfusion injury [Zingarelli B., Cardiovascular Research, 36, 205-215, 1997]. It is considered that the main cause of damages to the tissues is to be follow-up formation of the free radical during the reperfusion. During ischemia and reperfusion, some of typical ATP decent in many organism can be related to NAD+ deficiency which is derived from poly(ADP-ribos) conversion. Accordingly, PARP inhibition is expected to preserve cellular energy level, and subsequently to increase the survival of ischemic tissue after injury. Accordingly, PARP inhibitor is useful for treatment of cardiovascular diseases.
Recently, the potential of the PARP inhibitor for treatment of diabetic neuropathy has been suggested [Obrosova I G., Diabetes. 54(12), 3435-3441, 2005].
Until today, the development of the Poly(ADP-ribose)polymerase (PARPs) has been reported in below: INO-1001 (by Inotek Pharmaceuticals) is been developing cardiovascular indications and as a treatment of malignant melanoma. AG014699 (by Pfizer) is been developing as a treatment of malignant melanoma. BS-201 and Bs-401 (by Bipar Sciences) are been developing as a treat of cancer and pancreatic cancer, respectively. Additionally, AstraZeneca has been developing AZD2281 for treatment of breast cancer, and MGI Pharma has conducted a study of sensitizer for radiotherapy and chemotherapy [News, Nature biotechnology, 24(10), 1179˜1180, 2006].
However, development of the Poly(ADP-ribose)polymerase (PARPs) inhibitors in connection with neurodegenerative diseases, which has not proceeded in the research until today, is demended acutely in consideration of increasing aging population and better life quality.
Accordingly, it is imperative to develop Poly(ADP-ribose)polymerase (PARP) inhibitor which can minimize side-effects, particularly in the current situation where no noticeable treatment has been developed for the above-mentioned diseases.
The present inventors have been researched low molecular weight PARP inhibitor which can be used for treatment of various diseases derived from over-activation of the Poly(ADP-ribose)polymerase (PARP), prepared novel tricyclic derivatives, confirmed the superior PARP inhibitory activity of said composition, and thus completed the present invention.